The phenotype and proliferative potential of pro-static epithelial cells, from organogenesis to the development of androgen-independent growth, is modulated through interactions with the microenvironment: age and androgenic milieu represent two components of the microenvironment most clearly related to human prostate cancer. During organogenesis the urogenital sinus mesenchyme directs the morphogenesis and differentiation of the developing epithelial cells. In the adult, reciprocal interaction between the stroma and the epithelium maintains differentiation and controls proliferation. Perturbation of these homeostasis-maintaining interactions could represent a major early event in the genesis of prostate cancer resulting in dramatic phenotypic plasticity. Most tumors of the prostate demonstrate phenotypic characteristics of secretory epithelial cells, and this cell compartment has limited proliferative potential for self-replacement. However, an epithelial stem cell located in the basal cell compartment has limited proliferative potential for self replacement. However, an epithelial stem cell located in the basal cell compartment has been proposed. These stem cells (unlike the secretory epithelium) survive through androgen ablation and are capable of repopulating the luminal epithelial compartment with differentiated secretory epithelium under micro-environmentally-mediated androgen- regulation. Altered differentiation of transformed stem cells, with their inherent proliferative potential, in the androgen containing environment of early tumor formation would produce the "secretory" phenotype observed prostatic adenocarcinomas. Therefore, the working hypothesis of this proposal is that a pluripotent stem cell in the prostate is the principal target for neoplastic transformation and that continuous interaction of the evolving tumor cell with the microenvironment represents a critical factor modulating the tumorigenic phenotype throughout progression, including the hormone refractory phenotype. To validate this hypothesis the following Specific Aims are proposed: Aim 1. Compare/contrast the expression of growth factors, their cognitive receptors, and androgen- regulation of gene expression/growth of an androgen-responsive normal prostatic epithelial cell line (H-UNC-e) established from the H tumor. Aim 2. Establish a cohort of spontaneously tumorigenic cell lineages from the RP-e epithelial cell line. Aim 3. Determine if transplantation to the prostatic versus subcutaneous microenvironment, and/or host age, induces differential effects on the phenotypic of HUNC-e cells, RP-e cells and the spontaneously tumorigenic lineages. Aim 4. Establish whether ligand- independent activation of the androgen receptor by endogenous growth factors or peptide hormones facilitates androgen-independent growth.